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Familial hypercholesterolemia (FH) is a life-threatening hereditary condition, yet 90% of Australians with FH remain undiagnosed. Experts urge proactive genetic testing to identify children and families at risk.
Every year Australians lose loved ones prematurely to heart disease, often unaware that there was a genetic element involved, which could also impact them. Chronic high cholesterol contributes to almost 40% of coronary heart disease. Heart health specialists are highlighting a gap in diagnosis of individuals at risk of coronary heart disease due to inherited conditions.
Familial hypercholesterolemia, or FH, resulting from a single gene fault, is an inherited condition that from birth limits the body’s ability to remove low-density lipoprotein (LDL) cholesterol — often referred to as ‘bad cholesterol’ — from the bloodstream. Raised blood LDL levels significantly increase the risk of coronary heart disease.
Around 1 in 250 Australians harbour a FH gene fault and estimates suggest that 90% remain undiagnosed.
There may be no symptoms or signs in the early stages of FH. As the condition progresses, FH can be diagnosed through proactively ascertaining blood levels of total and LDL cholesterol, taking a family history, or looking for the presence of clinical signs such as fatty deposits under the skin or a ring around the cornea of the eye. Sadly, too often the later impacts of premature cardiovascular events, such as heart attack or stroke, reveal the diagnosis.
The only definitive means of diagnosing FH is genetic testing, but testing uptake is low. A recent study mapping key barriers to FH genetic testing in Australian health care settings found that health care professionals question the need for a genetic diagnosis given the availability and effectiveness of lifestyle changes and cholesterol-lowering medications such as statins for individuals with raised LDL levels, irrespective of the cause.
Expert commentaries consistently emphasise that this approach overlooks the key benefit of genetic testing: early, pre-symptomatic identification as well as cascade testing, which allows for testing of family members. Siblings, children and parents of an individual with an FH genetic fault have a 50% chance of harbouring the same fault; aunts, uncles and cousins have a 25% chance. Any relative diagnosed with FH through cascade testing for the family’s specific gene fault can then address the condition before symptoms appear and cardiovascular disease is progressed. Earlier pre-symptomatic identification in individuals and their at-risk genetic relatives enables long term prevention rather than treatment of coronary heart disease.
The low levels of uptake of FH genetic testing have particular significance in Australia where routine cholesterol testing is usually only recommended from the age of 45 years. This contrasts with guidelines from the United States’ National Heart, Lung, and Blood Institute, which recommends that first cholesterol tests in children take place between age 9 and 11 years.
Given that children as young as 8 years old diagnosed with FH are recommended to commence statin therapy, a significant proportion of the next generation are not currently benefiting from evidence-based, easily accessible treatment for their chronic, progressive, coronary disease risk factor.
The notion of cascade testing and identifying FH in asymptomatic children can often be perceived as confronting rather than a disease prevention opportunity. This is especially true if it raises concerns regarding starting cholesterol management medication at a young age. Yet there is robust evidence supporting the long term safety and effectiveness of statins for paediatric use in reducing early cardiovascular risks. A landmark study published in The New England Journal of Medicine in 2019, for example, undertook a 20-year follow-up of 184 children with FH into adulthood, demonstrating that early statin therapy significantly reduced the progression of arterial damage with no adverse effects on the children’s growth and development. Professional guidelines also sanction predictive or presymptomatic genetic testing in children where there is likely to be a direct medical benefit.
Family or general practitioners (GPs) play a pivotal role in facilitating decision-making about FH genetic testing. GPs routinely engage in interactions that provide crucial opportunities to identify individuals and families at risk of FH, such as collecting family histories and checking cholesterol levels. If there is no known family history of FH, GPs must refer patients to a specialist for decisions about FH genetic testing. If patients are first- or second-degree relatives of an ‘index case’ — the first family member diagnosed with FH — GPs can directly order FH genetic tests. Cascade testing is key to the prevention of ischaemic vascular disease.
Since 2020 in Australia, genetic FH testing has become more widely available through a Medicare rebate item number as a means of facilitating uptake. This approach made little impact on testing rates. Studies exploring implementation of other strategies to enhance adoption of FH genetic testing note that several countries have trialled centralised cascade testing systems, systematically inviting relatives of index cases for genetic testing. So-called ‘direct contact’ of relatives to enable FH testing has been ethically recognised for 20 years. A long-running trial of centralised cascade testing in the Netherlands identified 70% of their FH population. The Geisinger Health System in the United States has implemented a standardised genetic testing program, including routine FH testing into its care practices.
Implementation studies also identify a resistance to paediatric FH testing related to doctors having inadequate information to confidently engage in discussions about implications for young patients and their families. Additionally, while GPs have a solid understanding of cholesterol-lowering therapies particularly in their middle-aged and elderly patients, they may be less familiar with the hereditary nature, prevalence, earlier onset and diagnostic characteristics of FH.
A further complication is that even with a solid understanding of FH, ethical questions remain over who the primary beneficiary of paediatric testing ought to be. On the one hand, it can be argued that testing for FH in children should be undertaken as early as possible if the primary justification is to benefit other relatives. Yet if the focus is more tightly on benefits to the child tested, then this may justify waiting until they are able to commence statin therapies. Such tensions led the UK National Screening Committee’s ethics task group to suggest that a family-based framing may be justified in the case of paediatric testing for FH. On this view, the family unit is considered the beneficiary of FH testing, and decisions about when to test consider the interconnectedness of children and their parents.
Experts are urging proactive genetic testing and early treatment to prevent premature heart disease. The tools, protocols and international success stories to prevent the cardiovascular harm of FH are in place. In Australia, strategic implementation support is needed, including clear protocols for proactive FH testing and FH management in the case of paediatric diagnosis. Greater public discussion and open debate dialogue will help Australian families and health care professionals understand the benefits of early FH diagnosis, encourage proactive prevention and reduce preventable loss of life.
The author team is conducting research to understand more about genetic testing in general practice. If you are an Australian GP and would like to participate in a short interview, please contact Romika Patel at romika.patel@mq.edu.au
Klay Lamprell, PhD, is a Research Fellow at the Australian Institute of Health Innovation, Macquarie University, Sydney. Klay studies ways to improve early diagnosis of cancers and inherited conditions through primary care interventions, including genomic applications in primary care.
Mitchell Sarkies, PhD, is a Senior Lecturer, Sydney Horizon Fellow and NHMRC Emerging Leadership Fellow at the Sydney School of Health Sciences and leads the Innovation and Methods Stream for the Sydney Health Partners Implementation Science Program.
Associate Professor Alison Trainer, PhD, MSc , FRACP, is a clinical geneticist based at the Royal Melbourne Hospital and Peter MacCallum Cancer Centre. Her research focusses on the development of digital approaches to ensuring equitable access to genetics tests, and empowering consumers live with a genetic diagnosis.
Gabriel Watts, PhD, is a postdoctoral research fellow with Sydney Health Ethics at the University of Sydney.
Ainsley Newson, PhD, is Professor of Bioethics at Sydney Health Ethics, Faculty of Medicine and Health, the University of Sydney. She has researched the ethical aspects of genetics and genomics for over 25 years and has particular interest in both the impact of genomic information in families and the use of genomic screening in population health settings.
Jeffrey Braithwaite, PhD, FFPHRCP (UK) is Founding Director of the Australian Institute of Health Innovation and Professor of Health Systems Research at Macquarie University, with professorial appointments at six international Universities. He leads research on how to improve care including studying patient safety, genomics, AI, climate change and learning health systems.
Associate Professor Janet Long, PhD, with the Australian Institute of Health Innovation at Macquarie University, studies the health system using a “big picture,” complexity lens to improve care quality, safety and efficiency. Research interests are genomic applications in primary care, access to generalist health services for people with a rare disease, and socio-professional networks and processes of healthcare.
The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.
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